The need to treat debilitating bone disorders, such as osteoporosis, has led to extensive research on the mechanism and regulation of continuous bone formation and resorption. In particular, an appropriate balance of osteoblasts, which function to form bone tissue, and osteoclasts, which function to resorb bone tissue, is required to maintain the structural integrity and proper functioning of the skeleton in spite of continuous metabolism. Any changes in this balance of metabolism, such as an increased bone resorption (either absolute, or an increase via decreased bone formation relative to bone resorption) can lead bone diseases or disorders. One of the most common diseases resulting from this imbalance is osteoporosis, which is characterized by a decrease in bone mass and deterioration in skeletal micro-architecture leading to an increased fragility and susceptibility to fractures. Other diseases which result from, or otherwise involve, alterations in bone resorption include, but are not limited to, Paget's Disease, primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, various cancers where resorption is increased, and rheumatoid arthritis.
Because of the serious disorders that may result from a metabolic imbalance, researchers have been interested in studying bone metabolism and the mechanism by which bone resorption and formation occurs, to ultimately develop a strategy for inhibiting resorption, and/or to improve bone mass and/or bone micro-architecture by stimulating osteoblast activity. However, the action of both osteoclasts and osteoblasts is controlled by a number of complex factors, and thus developing selective therapeutics has proven to be a difficult task.
One approach that has been taken for the development of novel therapeutics for bone disorders is inhibition of the osteoclast proton pump. Baron and coworkers have previously demonstrated that this proton pump is a vacuolar H+-ATPase (see, Blair et al., Science 1989, 245, 855–857; Finbow et al., Biochem. J. 1997, 324, 697–712; Forgac, M. Soc. Gen. Physiol. Ser. 1996, 51, 121–132). It has been shown that osteoclasts, to effect bone resorption, ultimately lower the pH in the sealed microcompartment which underlies their site of attachment to the bone surface (see, Baron et al., J. Cell. Biol. 1985, 101, 2210–2222), thus resulting in the acidic envionment required to dissolve the bone mineral and to allow degradation of the bone matrix by proteases. The osteoclast ultimately uses a proton pump (an ATP-dependent transport of protons) to achieve this acidification and thus any therapeutic inhibition of the osteoclast proton pump should lead to a decrease in bone loss or turnover. As a result, many novel therapeutics developed to reduce bone resorption have focused on the inhibition of the proton pump to prevent osteoclast activity and excessive bone resorption. For a discussion of the vacuolar H+-ATPase and inhibitors of vacuolar H+-ATPase see Farina et al., Exp. Opin. Ther. Patents 1999, 9, 157–168 and David, P. and Baron, R. “The Vacuolar H+-ATPase: A Potential Target for Drug Development in Bone Diseases” Exp. Opin. Invest. Drugs 1995, 4, 725–740.
In addition to the inhibition of the proton pump, studies have also been directed towards the control of signal transduction to ultimately affect osteoclast or osteoblast function. For example, studies have provided evidence that Src protein kinases play a cruical role in osteoclastic function, and it has been shown in different cell types that phosphorylation by Src, and related kinases, of proteins proposed to participate or regulate the cytoskeletal architecture is one important requirement for their proper function (see, for example, “A Novel Inhibitor of the Tyrosine Kinase Src Suppresses Phosphorylation of Its Major Cellular Substrates and Reduces Bone Resorption In Vitro and in Rodent Models In Vivo” Missbach et al., Bone 1999, 24, 437–449). Because the cytoskeleton plays an important role in osteoclast motility, attachment, and formation of the sealing zone, it is likely that these cytoskeletal proteins may influence osteoclast function. Thus, agents which inhibit or promote interactions with Src or related kinases, are likely to affect cytoskeletal proteins and ultimately affect osteoclast function. Several compounds have been reported as inhibitors of tyrosine Src kinase and thus may be of some use in the inhibition of osteoclast-mediated bone resorption (see, for example, Missbach et al., Bone 1999, 24, 437–449; Connolly et al., Bioorg. & Med. Chem. Lett. 1997, 7, 2415–2420; Trump-Kallmeyer et al., J. Med. Chem. 1998, 41, 1752–1763; Klutchko et al., J. Med. Chem. 1998, 41, 3276–3292; Legraverend et al., Bioorg. & Med. Chem. 1999, 7, 1281–1293; Chang et al., Chem. & Biol. 1999, 6, 361–375; Lev et al. Nature 1995, 376, 737–784; Palmer et al., J. Med. Chem. 1997, 40, 1519–1529.
As described above, many of the existing therapeutics that have been developed for the treatment of bone disorders such as osteoporosis, involve the inhibition of osteoclast activity. For example, estrogens, bisphosphonates, calcitonin, flavonoids, selective estrogen receptor modulators are believed to act by the inhibition of osteoclast activity. Additionally, more recently, novel therapeutics have been developed to promote a fast increase in bone mineral content by promoting osteoblast activity. Such examples include peptides from the parathyroid hormone family, strontium ranelate, and growth hormone and insulin-like growth response (see, for example, “Promising New Agents in Osteoporosis”, Reginster et al. Drugs R & D 1999, 3, 195–201). Unfortunately, a significant problem of many of these therapetic agents, however, is that they are not specific enough for bone tissue and thus may lead to unwanted adverse side effects. Significant problems with bisphosphonates, for example, are well known. See e.g. Ezra and Golomb, Advanced Drug Delivery Reviews 2000, 42, 175–195.
Clearly, as evidenced by the number of different approaches to the available therapeutic agents, bone metabolism is controlled by a variety of factors. A common theme, however, is the desire to develop selective inhibitors or promoters of osteoclast or osteoblast activity, respectively. Although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, there remains a need to develop potent and selective agents having minimal side effects. More generally, there remains a need to develop compounds that can regulate cellular signal transduction pathways to inhibit or promote complex biological processes in order to treat and/or prevent diseases mediated by such signaling.